The neurological consequences of diabetes exclusively affect the peripheral nervous system (PNS) and are linked to hypermetabolic activity in the sorbitol pathway and intrinsic microvascular changes which have long-term structural consequences. Hyperglycemia is the underlying defect and since nerves are insulin-independent, excess glucose enters the endoneurium being converted into osmotically active polyols. Transport mechanisms which convey hexoses across the blood-nerve barrier also carry sodium into the endoneurium resulting in increased osmotic activity associated with reduced nerve conduction velocity and reduced nerve fiber diameter in the early metabolic phase, during which neuropathy is most amenable to treatment with aldose reductase inhibitors and insulin. Our studies focus i) on the link between increased sodium and electrophysiologic disturbances, ii) fine structural localization of increased sodium in the axon and paranodal region and iii) mechanisms of glycogen accumulation in diabetic axons. In the latter stages of the disease microcirculatory changes become established and have an impact on the nerve fiber in which axonal degeneration and demyelination occur. Microangiopathy, resulting in narrowing of the capillaries, is implicated and the proposed research attaches particular significance to the transperineurial microcirculation which may play a key role in the pathogenesis of endoneurial ischemia. Both hyperglycemia and hypoxia are underlying mechanisms whose contributions to pathogenesis will be individually investigated using new techniques for measurement of nerve blood flow, endoneurial electrolyte analysis by x-ray microprobe, nerve oxygen tension and endoneurial fluid pressure. Biophysical techniques designed to investigate disturbances in the endoneurial microenvironment will be combined with classic morphologic and morphometric methods to determine the pathogenesis of the early changes in diabetic neuropathy knowledge of whose onset is crucial to initiate appropriate treatment before irreversible neuropathic changes supervene.